Cholecystokinin (CCK), a polypeptide hormone that is released from the intestine during feeding, stimulates pancreatic exocrine secretion, gallbladder contraction, and bowel motility. Because of prior difficulties in measuring blood levels of CCK, little is known about the physiology and pathology of the hormone. The principal investigator has recently developed a sensitive and specific bioassay for measuring both fasting and postprandial plasma levels of CCK and has demonstrated that physiological concentrations of CCK directly regulate beta cell function by potentiating amino acid-induced insulin secretion. Moreover, his preliminary studies in patients with non-insulin dependent diabetes mellitus (NIDDM) demonstrate abnormal CCK secretion in response to feeding a mixed liquid meal. The proposed research will examine the role of CCK in the impaired insulin secretion of NIDDM by investigating four well characterized groups of patients and their families described in Project 1. CCK secretion and action will be studied in: (1) non-diabetic subjects with relative insulin sensitivity, (2) non-diabetic subjects with relative insulin resistance, (3) those with insulin resistance and abnormal glucose tolerance, and (4) those with NIDDM. It will be determined whether there is an abnormality in either CCK secretion, or beta cell resistance to the actions of CCK in patients with impaired insulin secretion and whether such a defect can be corrected by the administration of CCK. Finally, it will be determined whether there are familial patterns of CCK secretion or action that contribute to abnormal secretion.